Inhibitors of rna helicase dhx9 and uses thereof

Abstract

Provided are compounds of the Formula (I):or pharmaceutically acceptable salts thereof, which are useful for the inhibition of DHX9 and in the treatment of a variety of DHX9 mediated conditions or diseases, such as cancer.

1 . A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is halo; 
 Y is O or NR y ; 
 R y  is H or C 1-4 alkyl; 
 R 1  is C 1-4 alkyl or C 3-6 cycloalkyl; wherein the C 1-4 alkyl or C 3-6 cycloalkyl are each optionally and independently substituted with 1 to 3 halo or —OH; 
 Ring A is a C 3-6 cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl; phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10-membered bicyclic heteroaryl; 
 m is 0 to 3; 
 n is 0 or 2; 
 each R 2  is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, halo, OR 2a , cyano, —NR 2b R 2c , —SO 2 R 2a , —C(O)R 2d , and —C(O)NR 2b R 2c , wherein the C 1-4 alkyl and C 3 , 6cycloalkyl are optionally substituted with 1 to 4 R 2e ; or 2 R 2  together form oxo; 
 R 2a  is H, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxyC 1-4 alkyl; 
 R 2d  is H, C 1-4 alkyl, C 3-6 cycloalkyl, OR 2a , phenyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 8-membered bicyclic heterocyclyl, or 5 to 6-membered monocyclic heteroaryl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 halo and the 5- to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 3 C 1-4 alkyl, C 1-4 haloalkyl, or phenyl; 
 R 2b  and R 2c  are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents independently selected from halo and C 1-3 alkoxy; or R 2b  and R 2c , together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R 2d ; 
 each R 2e  is independently selected from halo, cyano, NR 2b R 2c , OR 2a , phenyl, and 4 to 6 membered monocyclic heterocyclyl; 
 Z is a bond, —CH 2 —, —O—, —O—C 1-4 alkylene-*, —C 1-4 alkylene-O—*, —C(O)—, —C(O)O—*, —OC(O)—*, —S(O) 2 —, —S(O) 2 N(Za)-*, —N(Za)S(O) 2 —*, —N(Za)-, —N(Za)-C 1-4 alkylene-*, —C 1-4 alkylene-N(Z a )—*, —C(O)N(Z a )—*, or —C(O)N(Z a )—C 1-3 alkylene-*, wherein * indicates the attachment point to R 3 ; 
 Z a  is H or C 1-4 alkyl; 
 R 3  is C 3-6 cycloalkyl, 7 to 10-membered bicyclic carbocyclyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10-membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10-membered bicyclic heteroaryl, wherein the C 3-6 cycloalkyl, 7 to 10-membered bicyclic carbocyclyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10-membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10-membered bicyclic heteroaryl are each optionally and independently substituted with 1 to 4 R 4 ; 
 each R 4  is independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, OR 4a , cyano, —NR 4b R 4c , —C(O)R 4a , —C(O)OR 4a , —C(O)NR 4b R 4c , —NR 4b C(O)R 4a , —NR 4b C(O)OR 4a , —NR 4b SO 2 R 4a , —SR 4a , —S(O)R 4a , —SO 2 R 4a , —SO 2 NR 4b R 4c , —P(O)R 4b R 4c , phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl is optionally substituted with 1 to 4 R 4d , and wherein the phenyl, to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl and 6 to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R 4c  and further optionally substituted with 1 or 2 oxo; or two R 4  together form oxo; 
 R 4a  is H, C 1-4 alkyl optionally substituted with 1 to 4 R 4d , —NR 4b R 4c , C 3-6 cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the C 3-6 cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 R 4e ; 
 R 4b  and R 4c  are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and C 1-4 alkyl optionally substituted with 1 to 4 R 4d ; or R 4b  and R 4c  together with the nitrogen atom to which they are attached to form a 4 to 6-membered monocyclic heterocyclyl; 
 each R 4d  is independently selected from halo, OR 4f , —C(O)C 1-4 alkyl, —C(O)NR 4b R 4c , —C(O)C 1-4 haloalkyl, —C(O)OR 4f , —NR 4b R 4c , phenyl, and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 4g ; 
 each R 4c  is independently selected from halo, C 1-4 alkyl, cyano, OR 4f , —NR 4b R 4c , —C(O)H, —C(O)R 4h , —SO 2 C 1-3 alkyl, and —C(O)NR 4b R 4c , wherein C 1-4 alkyl is optionally substituted with 1 to 3 substitutes independently selected from halo, —SO 2 C 1-3 alkyl and —C(O)NR 4b R 4c ; or two R 4c  together form oxo; 
 R 4f  is H, C 1-4 alkyl, C 1-4 haloalkyl, phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo; 
 each R 4g  is independently selected from halo, OR 4f , C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, —NR 4b R 4c , —C(O)H, and —C(O)OR 4f ; and 
 each R 4h  is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy or —N(R 4b ) 2 . 
 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is:
 (a) Cl, Br, or F;   (b) Cl or Br; or   (c) Cl.   
     
     
         4 .- 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:
 (a) phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazoyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridin-6-yl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, pyrrolo[1,2-a]pyraziny, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, benzothiophenyl, thieno[3,2-d]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, 1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl;   (b)   
       
         
           
           
               
               
           
         
       
       each of which is substituted with 0 to 2 R 2  and 0 to 1 Z—R 3 ; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         (c) 
       
     
     
         7 .- 14 . (canceled) 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from —OCH 3 , cyclopropyl, —CH 3 , —CF 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CH 2 OH, —CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CN, —CH 2 CHF 2 , —CH 2 NH 2 , —N(CH 3 ) 2 , —SO 2 CH 3 , cyano, halo, —C(O)OH, —C(O)N(CH 3 ) 2 , and —C(O)NHCH 3 , or the following structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 (a) n is 1;   (b) n is 1 and Z is a bond; or   (c) n is 1 and Z is —CH 2 —, —CH(CH 3 )—, —O—, —N(H)—, —N(C 1-4 alkyl)-, or —C(O)NH—*, wherein * indicates the attachment point to R 3 .   
     
     
         18 .- 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from:
 (a) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazolyl, imidazoyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazoly, benzamidazolyl, indazolyl, indoyl, imidazolidinyl, azetidinyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, spiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, and 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with 1 to 3 R 4 ;   (b)   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       each of which is optionally substituted with 1 to 3 R 4 ;
 (c) 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 .- 31 . (canceled) 
     
     
         32 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 (a) R 4  is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, —OR 4a , —CN, —NH 2 , —NR 4b R 4c , halo, —C(O)R 4a , —NHC(O)R 4a , —NHC(O)OR 4a , —NR 4b SO 2 R 4a , —SR 4a , —S(O)R 4a , —SO 2 R 4a , —SO 2 NR 4b R 4c , —P(O)R 4b R 4c , —C(O)O—C 1-4 alkyl, benzyl, phenyl, 5 to 6-membered monocyclic heteroaryl, 6 to 10-membered bicyclic heterocyclyl, and 4 to 6-membered monocyclic heterocyclyl, wherein the C 1-3 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl represented by R 4  is optionally substituted with 1 to 3 substituents independently selected from halo, phenyl, 5 to 6-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 4g , and 4 to 6-membered monocyclic heterocyclyl optionally substituted with 1 or 2 R 4g , —C(O)NR 4b R 4c , —C(O)R 4a , and OR 4f ; and the benzyl, phenyl, 5 to 6-membered monocyclic heteroaryl, 6 to 10-membered bicyclic heterocyclyl, and 4 to 6-membered monocyclic heterocyclyl represented by R 4  are each optionally substituted with 1 to 3 R 4c  and further optionally substituted with one or two oxo, or two R 4  together form an oxo;   R 4a  is H, C 1-4 alkyl optionally substituted with 1 to 4 R 4d , —NR 4b R 4c , C 3-6 cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5 to 6-membered monocyclic heteroaryl are optionally substituted with 1 to 3 R 4e ;   each R 4b  is independently H or C 1-4 alkyl;   R 4 , is H, C 1-4 alkyl optionally substituted with 1 to 4 R 4d , 4 to 6-membered monocyclic heterocyclyl, or 5 to 6-membered monocyclic heteroaryl;   each R 4d  is independently selected from halo, —OR 4f , C 3-6 cycloalkyl, —C(O)OH, —NR 4b R 4c , phenyl, and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from C 1-3 alkyl, C 1-3 haloalkyl, halo, CN and OH;   each R 4e  is independently selected from halo, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, —C(O)R 4h , —SO 2 C 1-3 alkyl, —C 1-3 alkylSO 2 C 1-3 alkyl, —C(O)N(C 1-3 alkyl) 2 , and cyano; or two R 4c  together form an oxo;   R 4f  is H, C 1-4 alkyl, phenyl or 5 to 6-membered monocyclic heteroaryl, wherein phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 halo;   each R 4g  is independently C 1-3 alkyl or halo; and   each R 4h  is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxyl or —N(R 4 ) 2 ;   (b) R 4  is represented by the following structural formula:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       each of which is optionally substituted with 1 to 3 R 4e  and further optionally substituted with 1 or 2 oxo; or
 (c) R 4  is represented by the following structural formula: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         33 .- 37 . (canceled) 
     
     
         38 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4c  is independently —F, —CH 3 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 SO 2 CH 3 , —OH, —OCH 3 , —SO 2 CH 3 , —C(O)CH 3 , —C(O)cyclopropyl, —C(O)cyclobutyl, —C(O)cyclopentyl, —C(O)CH(CH 3 ) 2 , —C(O)C(CH 3 ) 3 —C(O)N(CH 3 ) 2 , —C(O)OCH 3 , or cyano. 
     
     
         39 .- 41 . (canceled) 
     
     
         42 . The compound of  claim 1 , wherein R 4  is —CH 3 , —CH 2 OH, —CHF 2 , —CF 3 , —CH(CF 3 )OH, —CH 2 OCH 3 , —CH 2 CN, —CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 C(O)N(CH 3 ) 2 , —C≡CC(CH 3 ) 2 OH, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —O-cyclopropyl, —O— cyclobutyl, —OC(CH 3 ) 3 , —OC(CH 3 ) 2 CH 2 OH, —OCH(CH 3 )C(O)OH, —OC(CH 3 ) 2 C(O)OH, —OCH(CH 3 )CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —CN, —NH 2 , —NHCH 3 , halo, —C(O)H, —C(O)CH(CH 3 ) 2 , —C(O)OCH 3 , —C(O)O-t-butyl, —N(CH 3 )SO 2 CH 3 , —NHC(O)CH 3 , —NHC(O)cyclopropyl, —NHC(O)OC(CH 3 ) 3 , —C(O)CH 3 , —C(O)OH, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —C(O)NC(CH 3 ) 3 , —SCH 3 , —S(O)CH 3 , —SO 2 CH 3 , —SO 2 N(CH 3 ) 2 , —P(O)(CH 3 ) 2 , phenyl, or R 4  is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         43 . (canceled) 
     
     
         44 . The compound of  claim 1 , wherein the compound is;
 (a) represented by Formula (IIA), (IIB), or (IIC):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; 
         (b) represented by Formula (IIIA) or (IIIB): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; or 
         (c) represented by Formula (IVA), (IVB), (IVC), or (IVD); 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1. 
       
     
     
         45 .- 46 . (canceled) 
     
     
         47 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —CH 3  or —CH 2 CH 3 . 
     
     
         48 . (canceled) 
     
     
         49 . The compound of  claim 1 , wherein the compound is represented by Formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is C 1  or Br; 
 R 1  is —CH 3  or —CH 2 CH 3 ; 
 ring A is selected from phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl; 
 m is 0 or 1; 
 each R 2  is independently selected from C 1-3 alkyl and —C(O)R 2d , wherein the C 1-3 alkyl is optionally substituted with R 2g ; 
 R 2d  is 4 to 6-membered monocyclic heterocyclyl; 
 R 2g  is cyano or OH; 
 R 3  is phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 or 2 R 4 ; 
 each R 4  is independently selected from halo, C 1-4 alkyl, —O-benzyl, —O—C 1-3 alkyl, cyano, —NH 2 , and 4 to 6-membered monocyclic heterocyclyl, wherein the benzyl is optionally substituted with 1 to 3 halo or C 1-3 haloalkyl. 
 
       
     
     
         50 . (canceled) 
     
     
         51 . The compound of  claim 49 , or a pharmaceutically acceptable salt thereof, wherein:
 (a) ring A is represented by the following formula:   
       
         
           
           
               
               
           
         
         (b) the compound is represented by Formula (IIB), (IIIA), (IVA); or (IVB): 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein m is O or 1; (c) R 3  is:
 (i) selected from phenyl, pyrazolyl, pyridyl, and pyrimidyl, each of which is optionally substituted with 1 to 2 R 4 ; 
 (ii) represented by the following structural formula: 
 
       
         
           
           
               
               
           
         
       
       each of which is optionally substituted with 1 to 2 R 4 ; or
 (iii) represented by the following structural formula: 
 
       
         
           
           
               
               
           
         
       
       (d) R 4  is —F, —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —CH 3 , cyano, —NH 2 , or R 4  is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         and/or 
         (e) R 2  is —CH 3 , —CH 2 CN, —CH 2 OH, or R 2  is represented by the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         52 .- 58 . (canceled) 
     
     
         59 . The compound of  claim 49 , wherein the compound is represented by Formula (IIB) or (IVB): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 m is 1; 
 R 1  is —CH 3 ; 
 X is C 1 ; 
 R 2  is —CH 3 ; 
 R 3  is pyrimidinyl or pyridinyl, each of which is optionally substituted with 1 or 2 R 4 ; 
 R 4  is halo, —OC 1-3 alkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the 4- to 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 halo or C 1-3 haloalkyl. 
 
       
     
     
         60 . The compound of  claim 59 , or a pharmaceutically acceptable salt thereof, wherein R 3  is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound of  claim 59 , or a pharmaceutically acceptable salt thereof, wherein each R 4  is independently —F, —OCH(CH 3 ) 2 , or —OC(CH 3 ) 3 , or R 4  is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         62 . The compound of  claim 1 , wherein the compound is selected from any one of Examples 1-736, or a pharmaceutically acceptable salt thereof. 
     
     
         63 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         64 . A method of treating a DHX9 mediated disease or disorder in a subject, comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 (a) the disease or disorder is cancer, viral infection or autoimmune disease;   (b) the disease or disorder is cancer;   (c) the disease or disorder is a cancer selected from colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, bladder, bone, soft-tissue, kidney, and liver cancer;   (d) the disease or disorder is a cancer selected from colorectal, endometrial, ovarian, hematopoietic, and gastric cancer; or   (e) the disease or disorder is Ewing's Sarcoma.   
     
     
         65 .- 68 . (canceled) 
     
     
         69 . The method of  claim 64 , wherein:
 (a) the cancer is a microsatellite instability (MSI) cancer;   (b) the cancer is a microsatellite instability-high (MSI-H) colorectal cancer;   (c) the cancer has mutations or defects in DNA mis-match repair (MMR), and/or mutations or defects in RNA splicing and the kinetochore complex.   
     
     
         70 .- 72 . (canceled)